CN102471326B - 硫杂苯并薁丙酸衍生物的制备方法 - Google Patents
硫杂苯并薁丙酸衍生物的制备方法 Download PDFInfo
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- CN102471326B CN102471326B CN201080032064.XA CN201080032064A CN102471326B CN 102471326 B CN102471326 B CN 102471326B CN 201080032064 A CN201080032064 A CN 201080032064A CN 102471326 B CN102471326 B CN 102471326B
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- Prior art keywords
- compound
- acid
- azulene
- general formula
- propionic acid
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- 238000004519 manufacturing process Methods 0.000 title claims abstract description 33
- 150000005599 propionic acid derivatives Chemical class 0.000 title abstract 4
- 150000001875 compounds Chemical class 0.000 claims description 43
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical group Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 27
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 24
- 238000000034 method Methods 0.000 claims description 16
- 238000002360 preparation method Methods 0.000 claims description 13
- 239000001257 hydrogen Substances 0.000 claims description 12
- 229910052739 hydrogen Inorganic materials 0.000 claims description 12
- 150000003839 salts Chemical class 0.000 claims description 10
- 125000000217 alkyl group Chemical group 0.000 claims description 9
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 8
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 claims description 7
- 239000002904 solvent Substances 0.000 claims description 7
- 229910052799 carbon Inorganic materials 0.000 claims description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 4
- 150000002431 hydrogen Chemical class 0.000 claims description 4
- 229910000042 hydrogen bromide Inorganic materials 0.000 claims description 3
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 claims 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 abstract description 44
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical group O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 abstract description 26
- 235000019260 propionic acid Nutrition 0.000 abstract description 22
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- 125000005605 benzo group Chemical group 0.000 description 32
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- SMZOUWXMTYCWNB-UHFFFAOYSA-N 2-(2-methoxy-5-methylphenyl)ethanamine Chemical compound COC1=CC=C(C)C=C1CCN SMZOUWXMTYCWNB-UHFFFAOYSA-N 0.000 description 8
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- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 6
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- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 6
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 5
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- 210000004556 brain Anatomy 0.000 description 5
- 229940125797 compound 12 Drugs 0.000 description 5
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- 239000008194 pharmaceutical composition Substances 0.000 description 5
- 238000001953 recrystallisation Methods 0.000 description 5
- 239000011780 sodium chloride Substances 0.000 description 5
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 4
- 206010041349 Somnolence Diseases 0.000 description 4
- GUGOEEXESWIERI-UHFFFAOYSA-N Terfenadine Chemical compound C1=CC(C(C)(C)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 GUGOEEXESWIERI-UHFFFAOYSA-N 0.000 description 4
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Abstract
本发明提供作为抗组胺剂等的有效成分有用的硫杂苯并薁丙酸衍生物的制备方法。通过本发明制备方法,可以制造作为硫杂苯并薁骨架的2位取代有丙酸的化合物的硫杂苯并薁丙酸衍生物,合成的硫杂苯并薁丙酸衍生物具有优异的组胺H1受体拮抗作用,并且显示低的脑内移行性,作为抗组胺剂等药物组合物的有效成分是有用的。
Description
技术领域
本发明涉及作为抗组胺剂等药物组合物的有效成分有用的硫杂苯并薁丙酸衍生物的制备方法。
背景技术
组胺(histamine)是作为诱发变态反应的化学介质的代表性物质,作为变态反应的原因的物质一旦进入体内,就会从肥大细胞、嗜碱细胞等细胞释放组胺。释放的组胺与组胺1型受体(H1受体)蛋白质结合,发挥降低血压、增强血管通透性、收缩平滑肌、扩张血管、促进腺分泌等药理作用,与变态反应、炎症的出现相关。这样,组胺与人的多种疾病相关联,通过抑制其作用,可以预防或治愈变态反应疾病、炎症。抑制组胺游离的药剂、阻碍与受体结合的药剂(抗组胺药)已大量市售,用于支气管哮喘、变态反应性鼻炎、花粉症、荨麻疹、特应性皮炎等疾病。
然而,由于迄今为止已知的抗组胺药出现基于中枢作用的镇静作用、困倦、头昏眼花、倦怠感等、基于抗胆碱作用的口渴、粘膜干燥感、视调节障碍等不期望的副作用,因此具有在开车前禁止服用等使用限制,成为使用不便的原因。因此,在患者和医疗现场需要可解决这样的问题且具有优异效果的抗组胺剂。本发明人发现了中枢性副作用少且具有强效的抗组胺作用的硫杂苯并薁丙酸衍生物的优异合成方法,从而完成了本发明。
关于具有9-10位间为双键的硫杂苯并薁骨架的哌啶衍生物,专利文献1中公开了,硫杂苯并薁骨架的2位被甲基、醇、烷基酮取代,哌啶的1位被烷基取代的具有神经阻断作用和中枢抑制作用的化合物。此外,专利文献2中公开了,同样的硫杂苯并薁骨架的2位被甲基、氯取代,哌啶的1位被烷基酮取代的具有镇静作用、睡眠促进作用和肌肉松弛作用的化合物。然而,关于可以由本发明制备方法合成的硫杂苯并薁骨架的2位键合有丙酸的化合物的合成方法,迄今为止尚未报告。
专利文献1:日本特开昭49-69677号公报
专利文献2:日本特开昭50-18478号公报
由于区域选择性地使丙酸的3位取代至硫杂苯并薁骨架在合成上有困难,因此合成了将乙氧基羰基乙烯基导入到硫杂苯并薁骨架的2位的化合物〔通式(I)的R2为乙基〕。此时,由于在哌啶环的1位〔通式(I)的R1〕预先导入有乙氧基羰基等保护基,因此为了合成的化合物的脱保护,进行通常所使用的溴化氢(HBr)乙酸处理。可是发现,随着作为目的的脱保护,硫杂苯并薁骨架2位侧链的乙烯基部分的双键转移至硫杂苯并薁骨架7元环部分(9-10位间)。通过本转移反应,可以制造硫杂苯并薁骨架的2位取代有丙酸的化合物、3-(4-哌啶-4-亚基-4H-1-硫杂苯并[f]薁-2-基)丙酸〔通式(II)中R1’和R2’为氢〕。该化合物的抗组胺作用优异且具有低的脑内移行性,因此作为困倦等中枢性副作用少的抗组胺剂等药物组合物的有效成分,有效性非常高。
发明内容
发明要解决的课题
本发明的目的是提供作为抗组胺剂等药物组合物的有效成分有用的硫杂苯并薁丙酸衍生物的制备方法。
用于解决课题的方法
迄今为止,尚未合成9-10位间为双键的硫杂苯并薁骨架的2位取代有丙酸的化合物。本发明制备方法基于下述新的合成方法:通过将硫杂苯并薁骨架的2位导入了羧基乙烯基、乙氧基羰基乙烯基等取代基的化合物〔通式(I)〕以溴化氢-乙酸等进行处理,从而使侧链取代基的乙烯基部分的双键转移至硫杂苯并薁骨架7元环部分(9-10位间)。通过本转移反应,可以制造硫杂苯并薁骨架的2位取代有丙酸的化合物硫杂苯并薁丙酸衍生物。
发明的效果
合成的硫杂苯并薁丙酸衍生物具有优异的组胺H1受体拮抗作用,此外,对小鼠口服给药时的脑内受体结合试验也显示低的脑内移行性,结果发挥减轻困倦等中枢性副作用的效果。因此,可以合成具有作为抗组胺剂等药物组合物的有效成分的期望特性的硫杂苯并薁丙酸衍生物的本发明制备方法,有效性非常高。
具体实施方式
本发明涉及下述通式(II)所示的化合物的制备方法,其特征在于,在甲酸、乙酸或丙酸溶剂中,使下述通式(I)所示的化合物与溴化氢、氯化氢、三氟化硼、甲磺酸或亚硫酰氯反应,
式中,R1和R1’各自相同或不同且表示氢或COOX,X表示烷基、或者可以具有取代基的苄基或苯基,R2和R2’各自相同或不同且表示氢、烷基、二苯基甲基、或者可以具有取代基的苄基或苯基。
在上述通式(I)和(II)中,作为“可以具有取代基”的取代基,可列举卤素、烷基、烷氧基、硝基、苯基等,该取代基不仅可以是一个,也可以是多个。
通式(I)和(II)中的烷基(包含上述取代基中的烷基)优选表示甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、戊基、异戊基、新戊基、叔戊基、己基、异己基等碳原子数1~6的直链或支链的烷基。
上述取代基中的卤素表示氟、氯、溴、碘等。此外,烷氧基优选表示甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、仲丁氧基、叔丁氧基、正戊氧基、正己氧基等碳原子数1~6的直链或支链的烷氧基。
在上述反应中,在乙酸、甲酸、丙酸等溶剂中,使通式(I)所示的3-(9,10-二氢-4H-1-硫杂苯并[f]薁-2-基)丙烯酸衍生物与与该衍生物等量或其量以上的酸性试剂例如氯化氢、溴化氢、碘化氢、三氟化硼、甲磺酸或亚硫酰氯优选在从室温至溶剂的沸点之间的适合温度下作用。通过该反应,利用上述酸对该衍生物的作用,丙烯酸部分的双键转移至环内,从而可以制造通式(II)所示的3-(4H-1-硫杂苯并[f]薁-2-基)丙酸衍生物。可以在反应时间为几十分钟~几小时的条件下进行,例如,在溴化氢-乙酸的情况下,90~100℃时为30分钟左右,50~55℃时为3小时左右,双键的转移反应完成。
在上述通式(I)的R1为乙氧基羰基等保护基的情况下,可以在上述双键的转移反应前通过碱处理进行脱离。在采用酸进行处理的情况下,在保护基脱离的同时发生双键的转移反应。与双键的转移反应相比,保护基的脱离反应需要时间,因此为了同时进行两反应,需要比双键的转移反应所需时间更长时间的反应。可以在双键的转移反应后,将叔丁氧基羰基(Boc基团)导入至通式(II)的R1’(参照实施例7、实施例10)。通过导入Boc基团,可以提高脂溶性,容易通过有机溶剂等进行纯化。可以按照通常的脱离反应,通过采用酸或碱进行处理来使Boc基团脱离。
在作为药物等的有效成分使用的情况下,需要非常高纯度的纯化物。因此,可以将由本发明制备方法合成的3-(4-哌啶-4-亚基-4H-1-硫杂苯并[f]薁-2-基)丙酸转化成盐来提高纯度。可以转化为例如有机磺酸(甲磺酸、乙磺酸等烷基磺酸、对甲苯磺酸、苯磺酸、萘磺酸等芳香族磺酸、樟脑磺酸、三氟甲磺酸等)、三氟乙酸、氢溴酸、氢碘酸、高氯酸、盐酸、硫酸、硝酸等的盐。还可以通过再结晶法而成为高纯度。可以适当选择向盐转化时的溶剂和再结晶法时的溶剂。
上述通式(I)和(II)所示的化合物包含它们的各种盐,可列举例如与盐酸、草酸、富马酸、对甲苯磺酸、马来酸、琥珀酸、乙酸、柠檬酸、酒石酸、碳酸、硝酸等形成的与酸的加成盐。此外,羧基的盐也可以包含钠、钾、钙等适当的碱金属和碱土类金属盐。这些盐可以通过公知的方法由游离的各化合物来制造,或可以相互转化。
实施例
接下来,列举实施例具体地说明本发明,但本发明不限于此。
熔点是将试样放入到玻璃毛细管中,采用ヤマトMP-21型熔点测定仪测定而得的(不进行温度计的校正)。MS光谱采用POLARIS Q(ThermoQuest社)测定。1H-NMR采用Bruker ARX500型核磁共振装置进行测定,化学位移值以作为内标而添加的TMS(δ=0ppm)为基准以ppm表示。硅胶柱色谱使用色谱用硅胶BW-127ZH(富士シリシア化学)来进行。薄层色谱使用硅胶F254(Merck,No.5715),采用UV灯和5%磷钼酸-乙醇显色试剂进行检测。
实施例1
4-(9,10-二氢-1-硫杂苯并[f]薁-4-亚基)哌啶-1-甲酸乙酯(化合物1)的制造
将市售的4-(9,10-二氢-1-硫杂苯并[f]薁-4-亚基)-1-甲基哌啶(200g)和三乙胺(30mL)的甲苯(1.5L)溶液加热至60℃,向该溶液中缓慢滴加氯甲酸乙酯(162mL)。在本反应中,由于最初剧烈反应,因此需要注意。滴加结束后,再加热回流1小时。自然冷却后,采用饱和氯化铵水溶液进行洗涤,将有机层通过硅胶短柱,采用5%乙酸乙酯-甲苯溶液2L溶出产物。减压蒸馏除去溶剂,向残渣中添加石油醚进行结晶。过滤出结晶并干燥,从而获得215g(90%)的化合物1。
Mp.110-113℃.MS(EI):m/z 353[M+].1H-NMR(DMSO-d6)δ:1.18(t,J=7.1Hz,3H),2.13-2.16(m,1H),2.18-2.23(m,1H),2.43-2.46(m,2H),2.80-2.83(m,2H),3.03-3.12(m,1H),3.17-3.28(m,3H),3.57-3.62(m,1H),3.69-3.71(m,1H),4.04(q,J=7.1Hz,2H),6.79(d,J=5.2Hz,1H),7.01-7.03(m,1H),7.17-7.21(m,2H),7.29-7.31(m,2H).
实施例2
4-(2-甲酰-9,10-二氢-1-硫杂苯并[f]薁-4-亚基)哌啶-1-甲酸乙酯(化合物2)的制造
将1,2-二氯乙烷(20mL)和DMF(4.1mL)的混合物利用冰浴进行冷却,在液体温度为0~5℃的范围内经0.5小时以上滴加磷酰氯(3.5mL)。将所得的混合物在室温再搅拌1小时,然后经1小时滴加化合物1(10.6g)的1,2-二氯乙烷(40mL)溶液。将反应混合物在50℃搅拌36小时,然后添加至碳酸钾(25g)水溶液(200mL)中。将混合物在室温搅拌1小时,然后分离有机层。将水层用二氯甲烷(50mL×3)萃取,与先前的有机层合并,用水(50mL)、饱和食盐水(50mL)进行洗涤,然后在无水硫酸钠上干燥。减压蒸馏除去溶剂,将所得的残渣油状物溶解在甲基叔丁基醚(100mL)中。当向该溶液中缓慢滴加正庚烷(400mL)时开始析出固体,因此静置30分钟。再添加正庚烷(400mL),然后减压浓缩直至溶剂为约200mL,然后滤取结晶,用正庚烷(30mL×2)进行洗涤。将所得的结晶在60℃减压干燥1小时,从而获得8.4g(73%)的化合物2。
Mp.146-149℃.MS(EI):m/z 381[M+].1H-NMR(DMSO-d6)δ:1.18(t,J=7.1Hz,3H),2.15-2.17(m,1H),2.26-2.29(m,1H),2.45-2.51(m,1H),2.81-2.91(m,2H),3.02-3.14(m,1H),3.16-3.43(m,3H),3.60-3.62(m,1H),3.72-3.75(m,1H),4.04(q,J=7.1Hz,2H),7.06-7.07(m,1H),7.19-7.24(m,2H),7.32-7.34(m,1H),7.76(s,1H),9.82(s,1H).
实施例3
3-[4-(1-乙氧基羰基哌啶-4-亚基)-9,10-二氢-4H-1-硫杂苯并[f]薁-2-基]丙烯酸(化合物3)的制造
向化合物2(100g)中添加吡啶(60mL)、哌啶(1mL)、丙二酸(32.4g),加热回流一晚。自然冷却,然后将反应混合物添加至2mol/L盐酸(740mL)中,将固化的产物充分弄碎,然后滤取结晶。将结晶用水(1L)洗涤,减压干燥,从而获得111g(100%)的化合物3。
Mp.228℃(dec.).1H-NMR(DMSO-d6)δ:1.18(t,J=7.0Hz,3H),2.08-2.14(m,1H),2.43-2.48(m,1H),2.49-2.53(m,2H),2.81-2.83(m,2H),3.01-3.15(m,1H),3.22-3.29(m,3H),3.57-3.59(m,1H),3.70-3.72(m,1H),4.05(q,J=7.0Hz,2H),6.00(d,J=15.7Hz,1H),7.02-7.04(m,1H),7.17-7.23(m,3H),7.30-7.32(m,1H),7.65(d,J=15.7Hz,1H).
实施例4
3-(4-哌啶-4-亚基-9,10-二氢-4H-1-硫杂苯并[f]薁-2-基)丙烯酸(化合物4)的制造
将化合物3(42.4g)和氢氧化钾(66g)添加至异丙醇(500mL)中,加热回流24小时。自然冷却,然后减压蒸馏除去溶剂直至半量,将水(500mL)添加至残渣中。用冰冷却混合物,利用2mol/L盐酸将pH调整至7。滤取析出的固体,然后用足够量的水进行洗涤,在50℃减压干燥,从而获得35.8g(85%)的化合物4。
Mp.269-272℃(dec.).MS(EI):m/z 351[M+].1H-NMR(DMSO-d6+三氟乙酸(5%))δ:2.32-2.39(m,1H),2.45-2.50(m,1H),2.60-2.67(m,1H),2.70-2.76(m,1H),2.81-2.90(m,2H),2.92-3.00(m,1H),3.05-3.13(m,1H),3.18-3.25(m,1H),3.28-3.38(m,3H),6.02(d,J=15.7Hz,1H),7.06-7.10(m,1H),7.18-7.26(m,2H),7.27(s,1H),7.32-7.36(m,1H),7.68(d,J=15.7Hz,1H),8.68-8.84(br,2H).
实施例5
3-(4-哌啶-4-亚基-4H-1-硫杂苯并[f]薁-2-基)丙酸(化合物5)的制造
(1)将30%HBr乙酸溶液(80mL)添加至化合物4(40g)和乙酸(800mL)的混合物中,然后在55℃~60℃搅拌3小时。自然冷却,然后减压蒸馏除去溶剂,将1mol/L氢氧化钠水溶液(400mL)添加至所得的残渣中,加热至40℃~50℃,再添加乙醇(200mL)来溶解。在持续加热至40℃~50℃的状态下适量添加1mol/L盐酸,将pH调整为7~8,然后在室温搅拌16小时。减压蒸馏除去乙醇,然后滤取析出的固体,用水(100mL×2)和乙醇(100mL×2)进行洗涤。在60℃将所得的固体减压干燥16小时,获得与噻吩环键合的丙烯酸的双键转移至7元环部分的化合物5的粗结晶32g(80%)。HPLC分析的结果是纯度为87%。
(2)上述操作(1)是将化合物3进行碱处理而脱离乙氧基羰基后的化合物4进行HBr乙酸处理,从而制造与噻吩环键合的丙烯酸的双键转移至7元环部分的化合物5的方法。作为另一方法,也可以将化合物3直接进行HBr乙酸处理,在进行乙氧基羰基的脱离反应的同时进行双键的转移反应,从而制造化合物5。
(3)将上述操作(1)中获得的化合物5的粗结晶(5g)添加至1.8mol/L氢氧化钠水溶液(35mL)中,加热回流,获得均匀的溶液。经1.5小时以上缓慢冷却至室温,然后滤取析出的固体,用1.8mol/L氢氧化钠水溶液(5mL×2)和二氯甲烷(5mL×2)进行洗涤。将所得的固体添加至水(100mL)中,加热回流,获得大致均匀的溶液。在90~100℃将1mol/L盐酸添加至该溶液中,将pH调整至7~8。自然冷却至室温,然后滤取产生的结晶,用水(5mL×2)和乙醇(5mL×2)进行洗涤。将所得的结晶添加至乙醇(100mL)中,加热回流1小时。自然冷却,然后滤取结晶,用乙醇(5mL×2)进行洗涤,在50~60℃减压干燥4小时,从而获得2.6g(回收率52%)的纯度99.6%(HPLC分析)的化合物5。
Mp.254℃(dec.).MS(EI):m/z 351[M+].1H-NMR(DMSO-d6)δ1.92-1.99(m,1H),2.14-2.20(m,1H),2.22-2.28(m,1H),2.38-2.44(m,1H),2.49(t,J=7.2Hz,2H),2.55-2.68(m,2H),2.83-2.94(m,2H),2.97(t,J=7.2Hz,2H),6.70(s,1H),6.83(d,J=11.5Hz,1H),6.89(d,J=11.5Hz,1H),7.09-7.13(m,1H),7.26-7.32(m 1H),7.36-7.40(m,2H).
实施例6
3-[4-(1-叔丁氧基羰基哌啶-4-亚基)-9,10-二氢-4H-1-硫杂苯并[f]薁-2-基]丙烯酸(化合物6)的制造
将化合物3(45.1g)和氢氧化钾(66g)添加至异丙醇(500mL)中,加热回流8小时。自然冷却,然后将水(500mL)添加至反应混合物中,加热至60℃,然后滴加二碳酸二叔丁酯(24g)的异丙醇(100mL)溶液。搅拌4小时,然后将反应溶液自然冷却至室温,减压蒸馏除去有机溶剂。将柠檬酸添加至残渣水溶液中使pH为4~5,滤取析出的固体,用水充分地洗涤。在50℃减压干燥24小时,从而获得44.9g(99%)的化合物6。
Mp.186℃(dec.).1H-NMR(DMSO-d6)δ:1.40(s,9H),2.08-2.14(m,1H),2.21-2.32(m,1H),2.41-2.53(m,2H),2.79-2.83(m,2H),3.01-3.15(m,1H),3.21-3.29(m,3H),3.51-3.54(m,1H),3.64-3.67(m,1H),6.00(d,J=15.7Hz,1H),7.02-7.04(m,1H),7.10-7.11(m,1H),7.16-7.23(m,2H),7.30-7.32(m,1H),7.52(d,J=15.7Hz,1H).
实施例7
3-[4-(1-叔丁氧基羰基哌啶-4-亚基)-4H-1-硫杂苯并[f]薁-2-基]丙酸(化合物7)的制造
(1)将化合物6(39.0g)溶解在乙酸(700mL)中,添加30%HBr乙酸溶液(162mL),在室温搅拌1小时。在100℃再搅拌1小时,然后减压蒸馏除去溶剂,从而获得包含Boc基团脱离且与噻吩环键合的丙烯酸的双键转移至7元环部分的化合物5的HBr盐的残渣。
(2)将水(200mL)、异丙醇(400mL)、2mol/L氢氧化钠水溶液(500mL)添加至该残渣中并溶解,滴加二碳酸二叔丁酯(21.9g)的异丙醇(100mL)溶液。在室温搅拌20小时,然后减压蒸馏除去有机溶剂,采用柠檬酸使水层为酸性。用二氯甲烷(100mL×3)萃取,然后合并有机层,用水(100mL)和饱和食盐水(100mL)进行洗涤,然后用无水硫酸钠进行干燥。减压蒸馏除去溶剂,将所得的残渣油状物用硅胶柱色谱(二氯甲烷∶丙酮=19∶1)纯化,将所得的油状物从石油醚结晶,获得22.5g(60%)的化合物7。
Mp.172℃(dec.).MS(EI):m/z 451[M+].1H-NMR(DMSO-d6)δ:1.39(s,9H),1.88-1.95(m,1H),2.08-2.15(m,1H),2.19-2.26(m,1H),2.34-2.40(m,1H),2.55-2.61(m,2H),2.99(t,J=7.2Hz,2H),3.06-3.22(m,2H),3.39-3.51(m,2H),6.73(s,1H),6.84(d,J=11.5Hz,1H),6.90(d,J=11.5Hz,1H),7.12-7.16(m,1H),7.27-7.32(m,1H),7.36-7.42(m,2H).
实施例8
3-(4-哌啶-4-亚基-4H-1-硫杂苯并[f]薁-2-基)丙酸(化合物5)的制造
将化合物7(13.5mmol)添加至甲酸(210mL)中,在室温搅拌2小时。减压蒸馏除去溶剂,然后将水添加至残渣中,再次减压蒸馏除去溶剂。将该操作重复3次,将乙醇(100mL)添加至析出的白色结晶中,并进行滤取,用乙醇(50mL)进行洗涤,从而获得9.71g(92%)的化合物5。
实施例9
4-[2-(2-乙氧基羰基乙烯基)-9,10-二氢-1-硫杂苯并[f]薁-4-亚基]哌啶-1-甲酸乙酯(化合物8)的制造
在氩气气氛下,在500mL圆底烧瓶中添加氢化钠(矿物油中60%)(3.6g),并用正己烷(50mL×3)进行洗涤。减压除去正己烷,然后在氩气气氛下添加无水THF(90mL)。在用冰冷却下经30分钟向该混合物中滴加磷酰基乙酸三乙酯(18mL)的无水THF(30mL)溶液,在室温再搅拌30分钟。在室温经1小时滴加化合物2(31.2g)的THF(200mL)溶液,然后再搅拌1小时。将反应混合物添加至冰水(500mL)中,然后分离有机层,将水层用乙酸乙酯(100mL×3)萃取。收集有机层并用水(100mL×2)和饱和食盐水(50mL)洗涤,然后用无水硫酸钠干燥。减压蒸馏除去溶剂,将所得的残渣油状物从石油醚结晶,获得化合物8的白色结晶29.7g(81%)。
Mp.90-93℃.MS(EI):m/z 451[M+].1H-NMR(DMSO-d6)δ:1.18(t,J=7.0Hz,3H),1.22(t,J=7.1Hz,3H),2.08-2.14(m,1H),2.43-2.48(m,1H),2.49-2.53(m,2H),2.81-2.83(m,2H),3.01-3.15(m,1H),3.22-3.29(m,3H),3.57-3.59(m,1H),3.70-3.72(m,1H),4.05(q,J=7.0Hz,2H),4.16(q,J=7.1Hz,2H),6.07(d,J=15.7Hz,1H),7.01-7.04(m,1H),7.17-7.23(m,2H),7.28(s,1H),7.30-7.32(m,2H),7.71(d,J=15.7Hz,1H).
实施例10
3-[4-(1-叔丁氧基羰基哌啶-4-亚基)-4H-1-硫杂苯并[f]薁-2-基]丙酸乙酯(化合物10)的制造
(1)将化合物8(9.0g)、乙酸(200mL)和30%HBr乙酸溶液(19mL)的混合物加热回流6小时。减压蒸馏除去溶剂,将所得的残渣油状物溶解于水(100mL)中,添加碳酸钾(20g),获得使乙氧基羰基脱离并且使与噻吩环键合的丙烯酸的双键转移至7元环部分的3-(4-哌啶-4-亚基-4H-1-硫杂苯并[f]薁-2-基)丙酸乙酯(化合物9)。
(2)在不离析化合物9的情况下在室温滴加二碳酸二叔丁酯(4.4g)的乙腈(100mL)溶液。在室温搅拌20小时,然后将反应混合物添加至水(100mL)中,用乙酸乙酯(50mL×3)进行萃取。合并有机层并用水(100mL)和饱和食盐水(50mL)洗涤,然后用无水硫酸钠干燥。减压蒸馏除去溶剂,将所得的油状物用硅胶柱色谱(己烷∶乙酸乙酯=9∶1)纯化,从而获得5.3g(55%)的作为油状物的化合物10。
MS(EI):m/z 479[M+].1H-NMR(DMSO-d6)δ:1.16(t,J=7.1Hz,3H),1.39(s,9H),1.88-1.96(m,1H),2.08-2.15(m,1H),2.19-2.26(m,1H),2.33-2.40(m,1H),2.59-2.72(m,2H),3.03(t,J=7.2Hz,2H),3.06-3.19(m,2H),3.39-3.51(m,2H),4.05(q,J=7.1Hz,2H),6.73(s,1H),6.84(d,J=11.5Hz,1H),6.90(d,J=11.5Hz,1H),7.11-7.16(m,1H),7.27-7.33(m,1H),7.37-7.42(m,2H).
实施例11
3-[4-(1-叔丁氧基羰基哌啶-4-亚基)-4H-1-硫杂苯并[f]薁-2-基]丙酸(化合物7)的制造
在室温将2mol/L氢氧化钠水溶液(11mL)添加至化合物10(5.3g)的乙醇(100mL)溶液中,搅拌20小时。减压蒸馏除去溶剂,然后将残渣溶解于水(50mL)中,添加柠檬酸(10g),用乙酸乙酯(50mL×3)萃取。合并有机层并用水(50mL)、饱和食盐水(50mL)洗涤,然后用无水硫酸钠干燥。蒸馏除去溶剂,将所得的残渣油状物用石油醚结晶,从而获得3.7g(74%)的化合物7。将化合物7与实施例8同样地处理,获得化合物5。
实施例12
4-(2-溴-9,10-二氢-1-硫杂苯并[f]薁-4-亚基)-1-甲基哌啶(化合物11)的制造
在0℃将溴(1.0mL)滴加至4-(9,10-二氢-1-硫杂苯并[f]薁-4-亚基)-1-甲基哌啶(5.76g)的氯仿(50mL)溶液中。在室温搅拌2小时,然后添加饱和碳酸氢钠水,分离有机层。将有机层用饱和食盐水洗涤,用无水硫酸钠干燥。减压蒸馏除去溶剂,将残渣用柱色谱(氯仿∶甲醇=9∶1)纯化,获得5.6g(91%)的作为白色结晶的化合物11。
Mp.141-142℃.MS(EI):m/z 375[M++2],373[M+].1H-NMR(DMSO-d6)δ:1.90-2.79(m,13H),3.18-3.22(m,2H),6.85(s,1H),6.98-7.30(m,4H).
实施例13
4-(2-溴-9,10-二氢-1-硫杂苯并[f]薁-4-亚基)哌啶-1-甲酸乙酯(化合物12)的制造
将氯甲酸乙酯(32mL)添加至化合物11(21.0g)的甲苯(200mL)溶液中,加热回流6小时。自然冷却,然后将反应混合物添加至饱和碳酸氢钠水中并分离有机层。将有机层用饱和食盐水洗涤,用无水硫酸钠干燥,然后减压蒸馏除去溶剂,将残渣用柱色谱(己烷∶乙酸乙酯=19∶1)纯化,从而获得15.0g(62%)的作为油状物的化合物12。
MS(EI):m/z 433[M++2],431[M+].1H-NMR(DMSO-d6)δ:1.17(t,J=7.1Hz,3H),2.10-2.23(m,2H),2.38-2.48(m,2H),2.68-2.83(m,2H),2.92-3.26(m,4H),3.52-3.78(m,2H),4.04(q,J=7.1Hz,2H),6.90(s,1H),7.02-7.13(m,1H),7.16-7.36(m,3H).
实施例14
4-(2-溴-9,10-二氢-1-硫杂苯并[f]薁-4-亚基)哌啶-1-甲酸乙酯(化合物12)的制造
在室温将溴(10.9mL)滴加至化合物1(50g)的氯仿(500mL)溶液中,搅拌2小时。将反应混合物用硫代硫酸钠水溶液(100mL)、饱和碳酸钾水溶液(100mL)依次洗涤,将有机层用无水硫酸钠干燥。减压蒸馏除去溶剂,将残渣用硅胶柱色谱(己烷∶乙酸乙酯=9∶1)纯化,从而获得67g(100%)的化合物12。
实施例15
4-[2-(2-乙氧基羰基乙烯基)-9,10-二氢-1-硫杂苯并[f]薁-4-亚基]哌啶-1-甲酸乙酯(化合物8)的制造
在氩气气流下,向化合物12(8.80g)的DMF(50mL)溶液中添加丙烯酸乙酯(18.5mL)、三乙胺(24mL)、乙酸钯(0.3g)和三(邻甲苯甲酰)膦(2.0g),在80℃搅拌一晚。自然冷却,然后将水添加至反应混合物中,用乙酸乙酯萃取,将有机层用饱和食盐水洗涤,然后用无水硫酸钠干燥。减压蒸馏除去溶剂,将残渣用柱色谱(己烷∶乙酸乙酯=9∶1)纯化,从而获得6.1g(79%)的化合物8。
实施例16
3-(4-哌啶-4-亚基-4H-1-硫杂苯并[f]薁-2-基)丙酸(化合物5)的制造
将30%HBr乙酸溶液(3.8mL)添加至化合物8(6.10g)的乙酸(50mL)溶液中,在120℃搅拌4小时,将反应物自然冷却至室温。分析反应产物,结果确认了,生成乙氧基羰基脱离并且与噻吩环键合的丙烯酸部分的双键转移至7元环部分的化合物9。接着,减压蒸馏除去溶剂,将所得的残渣溶解于乙醇(50mL)中,添加2mol/L氢氧化钠水溶液(14mL),在室温搅拌3小时。蒸馏除去溶剂,然后将水添加至残渣中,采用稀盐酸将该水溶液的pH调整至7,用氯仿萃取,从而获得化合物5。
实施例17
3-(4-哌啶-4-亚基-4H-1-硫杂苯并[f]薁-2-基)丙酸(化合物5)的对甲苯磺酸盐的制造和再结晶
(1)使化合物5(4.0g,纯度96.9%)分散在丙酮(120mL)中,在室温添加对甲苯磺酸一水合物(2.16g)。搅拌1小时,然后滤取析出的结晶,用丙酮(20mL)洗涤,从而以纯度99.1%获得化合物5的对甲苯磺酸盐4.5g(收率75%)。
(2)将上述产物1.0g添加至水、异丙醇、环戊基甲基醚(3∶37∶60)的混合溶剂(13mL)中,加热回流使其完全溶解,然后自然冷却至室温,滤取析出的结晶,用先前的混合溶剂(5mL)洗涤,从而获得纯度99.8%的3-(4-哌啶-4-亚基-4H-1-硫杂苯并[f]薁-2-基)丙酸对甲苯磺酸盐0.68g(回收率68%)。
实施例18
3-(4-哌啶-4-亚基-4H-1-硫杂苯并[f]薁-2-基)丙酸(化合物5)的苯磺酸盐的制造和再结晶
(1)使化合物5(4.0g,纯度96.9%)分散在丙酮(120mL)中,在室温添加苯磺酸一水合物(2.02g)。搅拌15小时,然后滤取析出的结晶,用丙酮(20mL)洗涤,从而以纯度99.9%获得化合物5的苯磺酸盐2.7g(收率46%)。
(2)将纯度99.6%的3-(4-哌啶-4-亚基-4H-1-硫杂苯并[f]薁-2-基)丙酸苯磺酸盐(1.0g)在丙酮(50mL)中加热并溶解,然后自然冷却至室温,滤取析出的结晶,从而获得纯度100%的3-(4-哌啶-4-亚基-4H-1-硫杂苯并[f]薁-2-基)丙酸苯磺酸盐0.30g(回收率30%)。
实施例19
3-(4-哌啶-4-亚基-4H-1-硫杂苯并[f]薁-2-基)丙酸(化合物5)的甲磺酸盐的制造和再结晶
使化合物5(0.5g,纯度96.9%)分散在丙酮(10mL)中,在室温添加甲磺酸(0.14g)。搅拌40小时,然后滤取析出的结晶,用丙酮(2mL)洗涤,从而以纯度98.7%获得化合物5的甲磺酸盐0.49g(收率77%)。
实施例20
3-(4-哌啶-4-亚基-4H-1-硫杂苯并[f]薁-2-基)丙酸(化合物5)的盐酸盐、硫酸盐、硝酸盐的制造
(1)使化合物5(0.5g,纯度96.9%)分散在丙酮(10mL)中,在室温添加2mol/L盐酸(0.9mL)。搅拌1小时,然后滤取析出的结晶,用丙酮(2mL)洗涤,从而以纯度98.2%获得化合物5的盐酸盐0.39g(收率71%)。
(2)将化合物5(4.0g,纯度96.9%)溶解于甲酸(80mL)中,在用冰冷却下添加浓硫酸(1.13g)。搅拌1小时,然后减压蒸馏除去溶剂,将水(40mL)添加至所得的残渣中,滤取析出的结晶,用冷水(2mL)洗涤,从而以纯度97.4%获得化合物5的硫酸盐0.39g(收率76%)。
(3)使化合物5(0.5g,纯度96.9%)分散在水(40mL)中,在用冰冷却下添加70%硝酸(0.2mL)。搅拌1小时,然后滤取析出的结晶,用水(2mL)洗涤,从而以纯度98.4%获得化合物5的硝酸盐0.39g(收率71%)。
实施例21
3-(4-哌啶-4-亚基-4H-1-硫杂苯并[f]薁-2-基)丙酸(化合物5)的盐酸盐的制造
使化合物5(2.85kg,纯度99.8%)分散在加热至80℃~90℃的水(37kg)中,搅拌30分钟。添加2mol/L盐酸(4.1kg),在该温度搅拌30分钟,溶解化合物5。在保持温度的状态下滤去不溶物,然后将2mol/L盐酸(2.05kg)添加至滤液中。将混合物冷却至10℃~20℃,搅拌17小时。滤取析出的结晶,用水(2L×3)洗涤,然后在60℃~65℃干燥48小时,从而以纯度99.91%获得化合物5的盐酸盐2.79kg(收率88.7%)。
产业可利用性
根据本发明制备方法,基于通过将硫杂苯并薁骨架的2位导入了羧基乙烯基、乙氧基羰基乙烯基等取代基的化合物〔通式(I)〕以溴化氢-乙酸等进行处理,使侧链取代基的乙烯基部分的双键转移至硫杂苯并薁骨架7元环部分(9-10位间)这样的新的合成方法,从而可以制造硫杂苯并薁骨架的2位取代有丙酸的化合物。通过本发明制备方法合成的3-(4-哌啶-4-亚基-4H-1-硫杂苯并[f]薁-2-基)丙酸(化合物5)等具有优异的组胺H1受体拮抗作用,此外,在对小鼠经口给药时的脑内受体结合试验中也显示低的脑内移行性,结果发挥减轻困倦等中枢性副作用的效果。因此,可以合成具有作为抗组胺剂等药物组合物的有效成分的期望特性的上述化合物的本发明制备方法,有效性非常高。
Claims (7)
1.下述通式(II)所示的化合物的制备方法,其特征在于,在乙酸溶剂中,使下述通式(I)所示的化合物与溴化氢进行反应,
式中,R1和R1’各自相同或不同且表示氢或COOX,X表示碳原子数1~6的直链或支链的烷基,R2和R2’各自相同或不同且表示氢或碳原子数1~6的直链或支链的烷基。
2.根据权利要求1所述的制备方法,通式(II)的R1’和R2’都为氢。
3.根据权利要求2所述的制备方法,使用通式(I)的R1和R2都为氢的化合物。
4.下述通式(II)的R1’和R2’为氢的化合物的制造方法,使通式(II)的R1’或R2’为除了氢以外的基团的化合物的该基团脱离,来制造通式(II)的R1’和R2’为氢的化合物,
5.通式(II)的R1’和R2’都为氢的化合物转换为盐的方法,其特征在于,将根据权利要求2或权利要求4的制造方法得到的通式(II)的R1’和R2’都为氢的化合物进一步转化成盐
6.根据权利要求5所述的方法,盐为有机磺酸盐。
7.根据权利要求5所述的方法,盐为盐酸盐。
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US8536342B2 (en) | 2013-09-17 |
EP2460803B1 (en) | 2016-01-13 |
AU2010279164A1 (en) | 2012-02-02 |
EP2460803A1 (en) | 2012-06-06 |
TW201109320A (en) | 2011-03-16 |
WO2011013632A1 (ja) | 2011-02-03 |
JPWO2011013632A1 (ja) | 2013-01-07 |
CN102471326A (zh) | 2012-05-23 |
CA2768948A1 (en) | 2011-02-03 |
EP2460803A4 (en) | 2013-01-16 |
IL217495A (en) | 2014-12-31 |
IL217495A0 (en) | 2012-02-29 |
US20120123127A1 (en) | 2012-05-17 |
JP5606440B2 (ja) | 2014-10-15 |
TWI454470B (zh) | 2014-10-01 |
KR20120037913A (ko) | 2012-04-20 |
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